Lung cancer represents the most frequent form of malignancy comprising about in excess of one-quarter of all cancer clinical cased worldwide, while being concomitantly one of few cancer types with steadily increasing occurrence. Non-small cell lung carcinomas (NSCLC) are proven to be challenging tumor type for clinical management with frequent re-occurrence of drug resistant cancer after initial surgery/therapy and prominent metastatic potential. To gain in-depth insight into the molecular basis of lung carcinoma formation and reasons for drug resistance in relapse phase, the Center for Advanced Preclinical Research successfully adopted and characterized several models of NSCLC. We have recently successfully completed several studies with a Biotechnology Company that established the utility of their irreversible EGFR inhibitor in the regression of LA harboring the primary L858R EGFR mutant present in patient cancers and of those resistant to first line therapy that express the L858R/T790 mutant. For this experimental compound, we have applied continuous treatment strategy in tumor bearing mice carrying combined L858R/T790M EGFR mutations to promote the outgrowth of resistant cancerous foci in treated lung tissue. Subsequent molecular analyses of such lesions demonstrated the presence of yet another spectrum of missense mutations in EGFR molecule (most notably, C797S single amino acid alteration) driving resistance to third generation of irreversible RTK inhibitors. Resistant tumors harboring such mutations have been passages subcutaneously to confirm the resistance and establish a collection of test models for discovery and evaluation of therapeutics capable of overcoming aberrant signaling via now triple L858R/T790M/C797S mutant EGFR receptor. We have completed preclinical studies of another proprietary agent, including PK/PD/Tox and efficacy evaluation, in collaboration with a pharmaceutical company. We have also initiated an intramural collaboration aimed at efficacy testing of several photosensitizing agents in RTK-driven lung cancer models. Delivering on the mission of supporting CCR intramural research aimed at mitigating clinical impacts from lung carcinogenesis, CAPR supported the lung cancer research of CCR clinical investigator Dr. Udayan Guha by establishing a collection of patient-derived xenografts using patient samples from CCR clinical trial network in lung cancer patients. CAPR has completed several correlative co-clinical experiments to interrogate molecular basis of resistant disease and identify valid avenues to prevent and treat oligo-resistant recurrent lung malignancies.